A New Focus: "Good Cholesterol"

November 15, 2005

In the cardiology world, the last 10 years are often referred to as the age of the statins. These drugs, which lower low-density lipoprotein (LDL), often known as "bad cholesterol," were introduced in 1995. They have been so successful at reducing heart attacks and other adverse events of heart disease that they are now the best-selling medicines in the world.

Yet the latest data indicate that statins may not be able to improve health much more than they already have. That's why researchers are now focusing their attention on a new target: raising high-density lipoprotein (HDL), or "good cholesterol." LDL enables dangerous plaque to build up and clog artery walls, while HDL clears the plaque away.

There's no question that lowering LDL levels improves health. But the question many doctors have been asking is, "How low can we go?"

LOWER-LEVEL LIMITS. An important study presented on Nov. 15 at the American Heart Assn. (AHA) meeting tried to answer that question by comparing patients on high doses of Pfizer's (PFE) Lipitor, the best-selling statin, with patients on standard doses of Zocor, a statin made by Merck (MRK). It turned out, however, that high-dose Lipitor was no better at preventing deaths, acute heart attacks, or cardiac arrest than Zocor, even though the Lipitor group did achieve lower cholesterol readings -- an average of 81 milligrams per deciliter of blood, compared with 104 mg/dL for the Zocor group.

The lower readings offered some lesser benefits. The Lipitor group, for example, had 17% fewer nonfatal heart attacks. Nevertheless, the benefits were "more modest than we had expected," says Dr. Terje R. Pedersen, professor of medicine at Ulleval University Hospital in Oslo, Norway, and chief investigator of the study. "Maybe our findings indicate that we have gotten to the limits of what we can achieve in reducing mortality with statins."

His conclusion has been a common theme at the AHA's annual Scientific Sessions, held in Dallas from Nov. 13 to Nov. 16. Statins have reduced heart attacks and other adverse events of heart disease in the U.S. by one-third since they were introduced. Now, researchers are trying to address the other two-thirds.

PATENT PROBLEM. Recent studies have indicated that lower and lower levels of LDL might further reduce death rates from heart disease -- recent guidelines call for an LDL level of 70 in high-risk patients, a very tough goal to achieve. The Lipitor/Zocor study, however, raises concerns about how much weight a low LDL level should carry when assessing risk. "It could be that we've gotten LDL down as low as we can," says Dr. Steven Nissen of Cleveland Clinic, a leading cardiologist.

But Nissen isn't ready to abandon the goal of lower bad cholesterol. "I think doctors will look at all the information [in various studies] and see that lower levels provide some benefit. You will see a drift towards more intensive treatment, and I think that's a good thing."

Pfizer was hoping that the Lipitor/Zocor trial would prove the benefits of more intensive treatment.. Zocor is coming off patent next year, and Lipitor is sure to face competition from cheaper generic versions of the Merck drug. If a high dose of Lipitor could be shown to have benefits, Pfizer would have some leverage in convincing insurers to continue paying for the brand-name drug, rather than a cheaper generic.

Dr. Richard Karas, director of preventive cardiology at New England Medical Center in Boston, says doctors should not abandon the goal of getting LDL as low as possible, but they should also try to raise HDL. "The further down we go with LDL, the smaller and smaller the benefits." In addition, he notes that the higher the dose of any medication, the higher the risk of adverse events. "It's better to use modest doses of several medications," he says, and, in particular, to focus on drugs that can raise HDL.

"AGE OF HDL CONTROL"? Another study presented at the meeting demonstrated the advantages of raising HDL. Niaspan, made by Kos Pharmaceuticals (KOSP), targets HDL. In a study of 130 patients who were also taking statins, it not only increased HDL levels, but actually reversed the buildup of plaque in the arteries -- the first time such a result has been reported with a drug.

There are several other drugs in the pipeline that raise HDL, including Pfizer's torcetrapib, currently in late-stage trials. "We could be entering the age of HDL control," says Nissen. If so, good cholesterol may finally be getting its due.